Cardiac muscle and other excitable mmbranes must have strongly voltage-dependent conductance in order to function. The molecular basis of such mechanisms in vivo is unkown. Our project will investigate the voltage-dependent conductances induced in thin lipid membranes by alamethicin and its synthetc analogues at the single channel level. We have already demonstrated that analogues of alamethicin induce differing conductances and have shown that lipid composition is an important factor influencing the nature of the conductance. Further, drugs, thought to act by altering the membrane dipole potential, influence the conductance of cations and anions oppositely and alter the gating preperties of alamethicin in ways predicted by dipole potential analysis. By studying alamethicin and its synthetic analogues per se we plan to continue to elucidate the molecular mechanisms of alamethicin conductance. Further, by using alamethicin and other ionophores as probes, we hope to suggest a detailed model for how lipid composition and certain types of drugs can alter the voltage-dependent conductance mechanisms in excitable tissues of clinical importance.